ClinVar Genomic variation as it relates to human health

The L527P variant in the PDE6B gene has been reported previously in association with autosomal recessive retinitis pigmentosa (McLaughlin et al., 1995; Carss et al., 2017). The L527P variant is observed in 16/111,416 (0.0144%) alleles from individuals of non-Finnish European background in large population cohorts and no individuals were reported to be homozygous (Lek et al., 2016). The L527P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret L527P as a likely pathogenic variant.

The PDE6B c.1580T>C (p.Leu527Pro) missense variant has been reported in a compound heterozygous state in three individuals, including a sibling pair, with retinitis pigmentosa (McLaughlin et al. 1995; Carss et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.00015 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the limited evidence, the p.Leu527Pro variant is classified as a variant of unknown significance but suspicious for pathogenicity for the recessive form of retinitis pigmentosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS4,PM1,PM2,PP3,PP4.

The PDE6B c.1580T>C variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PM3. Based on this evidence we have classified this variant as Variant of Uncertain Significance.

The p.Leu527Pro variant in PDE6B was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2, PM3. Based on this evidence we have classified this variant as a Variant of Uncertain Significance. If you have any questions about the classification please reach out to the Pierce Lab.

For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PDE6B protein function. ClinVar contains an entry for this variant (Variation ID: 378339). This variant is also known as T>C transition at position 18075. This missense change has been observed in individual(s) with autosomal recessive PDE6B-related conditions (PMID: 7724547, 28041643, 28559085, 30998820). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs760766981, gnomAD 0.01%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 527 of the PDE6B protein (p.Leu527Pro).

Variant interpretted as Likely pathogenic and reported on 08/20/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.